1. Field of the Invention
The invention relates to a method for producing bone substitution material and a profiled body, which can in particular be produced using this method.
2. Description of the Related Art
Bone fractures and damage are serious health problems in all day clinical work. Common bone substitution materials are autografts, allografts, xenografts and various synthetic materials like polymers, metallic materials, composites and bioceramics. However, none of these materials provides a perfect solution in particular for guided bone healing because there always remain questions about mechanical stability, long-term in-vivo biocompatibility, and biodegradability.
Autograft sources, which are transplanted bone, for example from the iliac crest, show an excellent osteoinductivity—that means build-up of new bones by differentiation of osteogenic cells from less differentiated precursor cells—but they are not available in unlimited amounts and also require a secondary operation. In the case of allografts, that means a graft from one member of a species to a genetically different member of the same species, or xenografts, that means a graft from one member of a species to a member of a different species, there are concerns about a possible contamination with infectious material, such as, for example HIV, hepatitis or BSE).
Due to these reasons, there is an ongoing interest in synthetic sources for bone grafts because they can be highly biocompatible, nontoxic, biodegrabable, cause no immunological or irritating response, have excellent osteoconductivity and can be optimised for many specific applications. The term “osteoconductivity” refers to the growth of osteoblasts along a bone graft, that means build-up of real new bone tissue.
At the moment, the most prominent bone substitution materials are sintered calcium phosphate ceramics on the basis of hydroxyapatite (HAP; Ca5(PO4)3OH) or β-tricalcium phosphate (β-TCP; Ca3 (PO4)2) and mixtures of both, the so-called biphasic calcium phosphates; BCP. Their chemical composition is related to that of natural bone mineral which is a calcium-deficient carbonated hydroxyapatite, leading to a good biocompatibility in bone contact. The main difference between sintered hydroxyapatite and bone mineral is the higher crystallinity and the absence of carbonate of the former.
The mineral component of bone is a so-called “biological apatite” in which carbonate in an amount of about 3 to 5 percent by weight substitutes phosphate ions, and which also contains small amounts of other ions. In the following the term “percent by weight is abbreviated with “wt.-%”.
In addition, all biologically formed apatites in bone, dentin and mineralised tendons are nanocrystalline with enamel being the only exception. In terms of composition, bone mineral is only roughly comparable to sintered hydroxyapatite, due to the differences in carbonate content and particle size that influence the solubility.
This results in sintered hydroxyapatite having a much lower rate of biodegradation compared to the nanocrystalline bone mineral. If an acceptable lifetime in the body of about 2 to 5 years is desired, sintered hydroxyapatite ceramics are therefore not acceptable. The β3-TCP ceramics have a higher rate of biodegradation, but they have a different chemical composition than bone mineral.
If the biological performance of different bioceramics is compared, it must be noted that the biological incorporation of a bone graft is a physiological process controlled by the cells of the surrounding host bone, in particular osteoblasts and osteoclasts. This biochemical response is influenced by the geometry, the chemical composition and the morphological and mechanical properties of a given biomaterial.
Besides the problems of the biological incorporation of a bone graft related to bone fractures and damage, bone infections still represent a major problem in medicine. The main reason is the poor accessibility of the infected bone site by systemically administered antibiotics. Therefore, a local therapy is desired. It can be achieved by a suitable carrier for a controlled drug delivery system. A bone graft provides one possibility to realise such a carrier.
Currently, local treatments are mainly handled by implanting poly(methyl methacrylate) (PMMA) systems loaded with antibiotics into the infection site, for example as bone cements. However, PMMA implants are not biodegradable and either have to be removed after the healing process or remain in the implantation site like bone cements for the fixation of endoprostheses.
Thus, a resorbable biomaterial, allowing release of controlled amounts of an antibiotic ingredient with no second surgical procedure to remove it, would be advantageous, especially as bone substitution material.
Synthetic biomaterials have been used successfully in clinical applications as an alternative to autogeneous, xenogeneous and allogeneous bone graft materials. In case of ceramic materials like, for instance, calcium phosphate, the conventional ceramic manufacturing process involves the consolidation of powders by molding and sintering. Because high temperatures are involved in sintering processes, any active ingredient like a drug can only be added to the final implant.
Clinical practice further demands that a bone graft material is resorbed or dissolved within a reasonable time, that means that the implant is finally replaced by new bone tissue. This is not the case for sintered ceramics as they have a much lower solubility than the nanocrystalline carbonated bone mineral that is dissolved by osteoclasts. From the clinical point of view, the goal is a full integration of a bone graft into the dynamic human organism where bone is continuously dissolved and produced by remodelling. A further aim is to prepare biodegradable, mechanically stable implants which also contain bioactive compounds.
With respect to the implant itself, it should be noted that while a compact synthetic bioceramic shows good mechanical properties, only the surface of ceramic will be in contact with tissue. Usually there will be no ingrowth of bone but only a degradation starting from the surface. Consequently, compact materials achieve only a geometrical fixation.
However, while porous materials provide a mechanical interlock caused by ingrowth of bone tissue into the pores. Due to this reason, porous bioceramics are preferred in clinical practice.
In recent years, particular attention was paid to the synthesis of bioceramics with porous morphology to allow the ingrowth of bone tissue which further improves the mechanical fixation of the implant at the implantation site. If an implanted porous ceramic is progressively replaced by natural bone, its biomechanical properties more and more resemble those of natural bone. To introduce porosity into a ceramic object, various methods were developed.
The current methods to introduce porosity into a ceramic are mainly based on the admixture of a combustible organic material, like, for instance, a polymer, that burns away during firing, or on a water soluble salt that leaves free spaces in the resulting object after washing with water.
The first method allows to manufacture an interconnected pore system when polymer fibres are used. However, it requires high-temperature treatment, that means it leads to a highly crystalline, sintered ceramic material with a low rate of biodegradation.
A characteristic of this method is the potential for a wide variation of porosity and pore size by using different kinds of, in particular polymer, fibres as templates which act as porogens within the ceramic. The term “porogen” is used for a substance which acts as a spacer at locations where a pore is situated in the final product. However, to remove these organic templates, calcination is required which induces high-temperature processes.
Secondly, the salt-leaching method does not require annealing, but it usually leads to closed pores which do not form an interconnecting, natural bone-like pore network. Ma et al. described in their publication “Synthetic nano-fibrillar extracellular matrices with predesigned macropoprous architectures”, J. Biomed. Mater. Res. (2000), pages 430 to 438, for example, that they used sugar fibres and porous sugar disks as water-soluble porogens for poly-L-lactide. A porosity caused by pores being interconnected to each other, a so-called “interconnecting porosity”, was obtained; however, the porogens had to be oriented manually; a process that is not suitable for large-scale up-scaling.
However, there is no method available to produce materials with interconnecting porosity without sintering, except for mechanical hole-drilling. Thus, up to now it is in particular not possible to prepare an object with interconnecting pores of nanocrystalline, bone-mineral-like apatite because it would recrystallize during sintering.